Luo Yuxin, An Chenrui, Zhong Ke, Zhou Ping, Li Dan, Liu Hui, Guo Qing, Wei Wei, Pan Hen, Min Zheying, Li Rong, Yu Yang, Fan Yong
State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China; National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China; Key Laboratory of Assisted Reproduction, Ministry of Education, Peking University Third Hospital, Beijing 100191, China; Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Peking University Third Hospital, Beijing 100191, China.
Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China.
J Adv Res. 2025 Feb;68:115-129. doi: 10.1016/j.jare.2024.02.011. Epub 2024 Feb 24.
Advanced maternal age is associated with reduced implantation and pregnancy rates, yet the underlying mechanisms remain poorly understood, and research models are limited.
Here, we aim to elucidate the impacts of senescence on implantation ability by employing blastoids to construct a novel research model.
We used a novel three-dimensional system with totipotent blastomere-like cells (TBLCs) to construct TBL-blastoids and established senescence-related embryo models derived from oxidative stress-induced TBLCs.
Morphological and transcriptomic analyses revealed that TBL-blastoids exhibited characteristic blastocyst morphology, cell lineages, and a higher consistency in developmental rate. TBL-blastoids demonstrated the ability to develop into postimplantation structures in vitro and successfully implanted into mouse uteri, inducing decidualization and forming embryonic tissues. Importantly, senescence impaired the implantation potential of TBL-blastoids, effectively mimicking the impaired implantation ability and reduced pregnancy rates associated with advanced age. Furthermore, analysis of differentially expressed genes (DEGs) in human homologous deciduae revealed enrichment in multiple fertility-related diseases and other complications of pregnancy. The genes implicated in these diseases and the common DEGs identified in the lineage-like cells of the two types of TBL-blastoids and deciduae may represent potential targets for addressing impaired implantation potential.
These results unveiled that TBL blastoids are an improved model for investigating implantation and early postimplantation, offering valuable insights into pregnancy-related disorders in women with advanced age and potential targets for therapeutic interventions.
高龄产妇与着床率和妊娠率降低有关，但其潜在机制仍知之甚少，且研究模型有限。
在此，我们旨在通过利用类囊胚构建一种新型研究模型，阐明衰老对着床能力的影响。
我们使用了一种具有全能性卵裂球样细胞（TBLCs）的新型三维系统来构建TBL-类囊胚，并建立了源自氧化应激诱导的TBLCs的衰老相关胚胎模型。
形态学和转录组学分析表明，TBL-类囊胚表现出典型的囊胚形态、细胞谱系，且发育率具有更高的一致性。TBL-类囊胚在体外表现出发育为着床后结构的能力，并成功植入小鼠子宫，诱导蜕膜化并形成胚胎组织。重要的是，衰老损害了TBL-类囊胚的着床潜力，有效模拟了与高龄相关的着床能力受损和妊娠率降低。此外，对人同源蜕膜中差异表达基因（DEGs）的分析揭示了多种与生育相关疾病和其他妊娠并发症中的富集情况。这些疾病中涉及的基因以及在两种类型的TBL-类囊胚和蜕膜的谱系样细胞中鉴定出的常见DEGs可能代表了解决着床潜力受损的潜在靶点。
这些结果表明，TBL类囊胚是研究着床和着床后早期阶段的改进模型，为高龄女性妊娠相关疾病提供了有价值的见解以及治疗干预的潜在靶点。
